Francisella tularensis (Ft) SchuS4 strain, the causative agent of tularemia, is amongst the most deadly potential agents of biological warfare and bioterrorism. One critical characteristic of Ft is its ability to dampen or subvert the functions of the cells primarily involved in innate immune defenses. Recent studies have shown that Ft infection leads to rapid replication of this bacterium in the host. Despite an explosive increase in bacterial numbers, the activation of macrophages and neutrophils is markedly suppressed. In addition, Ft exerts a profound suppressive effect on the induction of pro-inflammatory cytokines by blocking signal transduction pathways. However, the Ft-encoded factors responsible for this immune subversion remain largely unidentified. No virulence-associated secretion systems, secreted proteins, or toxins have been identified for this category A pathogen. Our preliminary studies reveal that Ft possesses unique mechanisms for subversion of innate immunity. We have observed that antioxidants of Ft not only scavenge reactive oxygen and nitrogen species (ROS/RNS) generated in response to the infection, but also interfere with signaling pathways to suppress pro-inflammatory cytokines and macrophage activation. Based on these observations, we have developed a hypothesis that links robust oxidant-scavenging capacity of Ft to its ability to suppress macrophage function. The central hypothesis of this application is that "antioxidant defenses of Ft alter redox-sensitive signaling components to suppress macrophage microbicidal activity". This application is aimed at understanding the virulence mechanisms of Ft that creates an environment permissive for its intramacrophage survival, growth and virulence. We propose to test this hypothesis via the following specific aims: Aim 1. Investigate how antioxidants of Ft SchuS4 subvert macrophage microbicidal activity. Aim 2. Determine the redox-sensitive components that control NF-kB signaling and pro- inflammatory cytokine responses. Aim 3: Establish the mechanism of suppression of NOD-like receptor (NLR) mediated signaling and inhibition of microbicidal activity by Ft antioxidants. The proposed studies are relevant to public health, as the re-emergence of Ft as an agent of bioterrorism poses a serious public health threat. Knowledge of Francisella factors that both suppress immunity and contribute to pathogenesis may lead to tularemia therapies and safer, more effective vaccines.